The preclinical (Pettit et al., 1995, Anti-Cancer Drug Design, 10, 299; 1995, Journal of Medicinal Chemistry, 38, 1666; 1998, Anti-Cancer Drug Design, 13, 183; Groslow et al., 1997, British Journal of Cancer, 81, 1318; Chaplin et al., 1999, Anticancer Research, 19, 189; Dark et al., 1997, Cancer Research, 57, 1829; Zhao et al., 1999, European Journal of Nuclear Medicine, 26, 236; Li et al., 1998, Int. J. Radiation Oncology Biol. Phys., 42, 899; Horsman et al., 1998, Int. J. Radiation Oncology Biol. Phys., 42, 895; Roberson et al., 1998, Mycol. Res., 102, 378) and clinical development (currently Phase I human cancer clinical trials), (Remick et al., 1999, Molecular Targets and Cancer Therapeutics Discover, Development, and Clinical Validation. Proceedings of the AACR-NCI-EORTC International Congress, Washington, D.C. #16, p. 4; Rustin et al., 1999, Molecular Targets and Cancer Therapeutics Discovery, Development, and Clinical Validation. Proceedings of the AACR-NCI-EORTC International Congress, Washington, D.C. #14, p. 4) of the powerful cancer antiangiogenesis (Pluda, 1997, Seminars in Oncology, 24, 203) natural product combretastatin A-4 (1a) and its sodium phosphate prodrug (1b) has stimulated a variety of new research endeavors directed at structural modifications. Illustrative are a new synthesis of the (Z)- and (E)-combretastatin A-4 (Lawrence et al., 1999, Synthesis, 9, 1656), synthesis of benzofuran (Banwell et al., 1999, Aust, J. Chem. 52, 767), diarylindole (Medarde et al., 1999, Bioorganic & Medicinal Chemistry Letters, 9, 2303), heterocombretastatin (Rey et al., 1999, Bioorganic & Medicinal Chemistry Letters, 9, 2711; Medarde et al., 1998, European journal of Medicinal Chemistry, 33, 71; Ohsumi et al., 1998, Journal of Medicinal Chemistry, 41, 3022) and combretadioxolane (Shirai et al., 1998, Bioorganic & Medicinal Chemistry Letters, 8, 1997) analogs. One of the most advanced (preclinical development) structural modifications of combretastatin A-4 is the L-serine amide of the amino replacement for the phenol group of stilbene 1a known as AC-7700 (Nihei et al., 1999, Japanese Journal of Cancer Research, 90, 1016).
The present invention is predicated upon a continued pursuit of further SAR studies of the most active constituents that earlier isolated from the Southern African bushwillow Combretum caffrum (Pettit and Rhodes, 1998, Anti-Cancer Drug Design, 13, 183), with a focus on synthetic conversions to phosphate salt prodrugs suitable for preclinical development. The present study was directed at obtaining useful diphosphate prodrugs based on combretastatin A-3 (2a, Pettit et al., 1987, Canadian Journal of Chemistry 65, 2390). The rational for targeting these new phosphate prodrugs was based on anticipated increases in aqueous solubility and transport in vivo to metastatic tumors, followed by rapid enzymematic cleavage of the phosphate ester bond by the greatly increased levels of phosphatases in the cancer tissue. Such exceptionally useful properties had been previously observed in the combretastatin A-4 phosphate prodrug. (See: Nabha et al. 2000, Anti-Cancer Drugs, 11, 385)